PROJECT SUMMARY Elucidating the neural circuit mechanisms underlying both homeostatic and uncontrolled motivation are crucial for developing better therapeutic treatments for neuropsychiatric disorders like depression or bipolar disorder. As part of mesolimbic brain reward circuitry, the ventral tegmental area (VTA) is generally reduced to its dopamine projection neurons. However, VTA also contains neurons that co-release inhibitory GABA and excitatory glutamate that are capable of powerfully modulating motivation. However, the functional role of this GABA/glutamate co-release in health and disease is not well understood. Why would these neurons simultaneously send both a `stop' and `go' signal? This set of proposed experiments will systematically test the hypothesis that VTA GABA/glutamate co- release serves as a mechanism to normalize postsynaptic activity in a homeostatic manner. Using optogenetics to drive VTA GABA/glutamate co-release in downstream structures that regulate mood and motivation, I will use chemogenetic approaches and chronic behavioral manipulations that alter postsynaptic activity, and then test the physiological and behavioral effect of optogenetically driving VTA GABA/glutamate co-release. These experiments will reveal basic mechanisms of neurotransmitter co-release and uncover their role within mesolimbic circuitry in modulating the switch between reward and aversion. The proposed experiments will also provide the investigator with extensive training in cell-attached and whole-cell patch clamp electrophysiology, and mouse genetics. Showing a brain mechanism capable of normalizing activity and in turn motivation can provide a novel target for treating neuropsychiatric diseases, as well as elucidate the mysterious role of neurotransmitter co- release beyond neuropsychiatric disease.